Novel sulfonic acid derivatives

ABSTRACT

A compound of the formula  
                 
 
or the pharmaceutically acceptable salt thereof; wherein X, Y, a, b, c, d, R 1 , R 2 , R 3  and R 5  are as defined above useful to treat inflammation and other immune disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This non-provisional application claims priority of U.S. provisionalapplication No. 60/299,461, filed Jun. 20, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to novel sulfonic acid derivatives,methods of use and pharmaceutical compositions containing them.

The compounds of the invention are potent and selective inhibitors ofMIP-1α (CCL3) binding to its receptor CCR1 found on inflammatory andimmunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1receptor is also sometimes referred to as the CC-CKR1 receptor. Thesecompounds also inhibit MIP-1α (and the related chemokines shown tointeract with CCR1 (e, RANTES (CCL5), MCP-2 (CCL8), MCP-3 (CCL7), HCC-1(CCL14) and HCC-2 (CCL15))) induced chemotaxis of THP-1 cells and humanleukocytes and are potentially useful for the treatment or prevention ofautoimmune diseases (such as rheumatoid arthritis, type I diabetes(recent onset), lupus, inflammatory bowel disease, optic neuritis,psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, andvasculitis), acute and chronic inflammatory conditions (such asosteoarthritis, adult Respiratory Distress Syndrome, RespiratoryDistress Syndrome of infancy, ischemia reperfusion injury, andglomerulonephritis), allergic conditions (such as asthma and atopicdermatitis), infection associated with inflammation (such as viralinflammation (including influenza and hepatitis) and Guillian-Barre),chronic bronchitis, xeno-transplantation, transplantation tissuerejection (chronic and acute), organ rejection (chronic and acute),atherosclerosis, restenosis (including, but not limited to, restenosisfollowing balloon and/or stent insertion), HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also have utility for theprevention of cancer metastasis. Compounds in this series may also limitthe production of cytokines at inflammatory sites, including but notlimited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g., fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria, etc.

MIP-1α and RANTES are soluble chemotactic peptides (chemokines) whichare produced by inflammatory cells, in particular CD8+ lymphocytes,polymorphonuclear leukocytes (PMNs) and macrophages, J. Biol. Chem., 270(30) 29671-29675 (1995). These chemokines act by inducing the migrationand activation of key inflammatory and immunomodulatory cells. Elevatedlevels of chemokines have been found in the synovial fluid of rheumatoidarthritis patients, chronic and rejecting tissue from transplantpatients and in the nasal secretions of allergic rhinitis patientsfollowing allergen exposure (Teran, et al. J. Immunol., 1806-1812(1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)).Antibodies which interfere with the chemokine/receptor interaction byneutralizing MIP1α or gene disruption have provided direct evidence forthe role of MIP-1α and RANTES in disease by limiting the recruitment ofmonocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704(1994) and Cook et al., Science, 269, 1583 (1995)). Together this datademonstrates that CCR1 receptor antagonists would be an effectivetreatment of several immune based diseases. The compounds describedwithin are potent and selective antagonists of the CCR1 receptor.

SUMMARY OF THE INVENTION

A compound of the formula

or the pharmaceutically acceptable salts and prodrugs thereof; wherein

-   -   a=0-5,    -   b=0-2,    -   c=0-2    -   d=0-4    -   X is —O—, —S—, —CH₂—, —NR⁶—    -   Y is (C₆-C₁₀)aryl, or (C₂-Cg)heteroaryl,    -   each R¹ is independently selected from the group consisting of:        H—, HO—, halo-, (C₁-C₈)alkyl- optionally substituted with 1-3        fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkyl group is        optionally substituted with 1-3 fluorine atoms,        HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-, HO—(C═O)—,        (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,        H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-;    -   each R² and R³ is independently selected from the group        consisting of: H—, oxo, (C₁-C₈)alkyl- optionally substituted        with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,        (C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,        (C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-,        H₂N—(C═O)—NH-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-SO₂—N H—(C₁-C₈)alkyl-,        (C₂-C₉)heteroaryl-(C₁-C₈)alkyl-, H₂N—(C═O)—,        H₂N—(C═O)—(C₁-C₈)alkyl-;    -   each R⁴ is independently selected from the group consisting of:        H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—, (C₁-C₈)alkyl-NH—,        [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionally substituted with 1-3        fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkyl group is        optionally substituted with 1-3 fluorine atoms,        HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-,        H₂N—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-,        [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—,        (C₁-C₈)alkyl-(C═O)-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,        (C₂-Cg)heteroaryl-, (C₆-C₁₀)aryloxy-, —SO₂NH₂,        —NHSO₂—(C₁-C₈)alkyl-, H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-NH—(C═O)—, (C₁-C₈)alkyl-NH—(C═O)-(C₁-C₈)alkyl-,        [(C₁-C₈)alkyl]₂N—(C═O)—, [(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-,        (C₃-C₈)cycloalkyl-, (C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-,        (C₁-C₈)alkyl-(C═O)—NH—, H₂N—(C═O)—NH—,        H₂N—(C═O)—NH—(C₁-C₈)alkyl-;    -   R⁵ is (C₁-C₈)alkyl-.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as, but not limited to, the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (eq-, potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

The present invention also relates to compounds of formula I wherein anyof the hydrogens may optionally be replaced by deuterium.

Unless otherwise indicated, the alkyl groups referred to herein may belinear or branched, and they may also be cyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) or bicyclic (e.g.,norbornanyl, bicyclo [3.2.1]octane) or contain cyclic groups. They mayalso contain zero to two levels of unsaturation and may be optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of but not limited to halo-, HO—, NC—, H₂N—, HO—(C═O)—.

Unless otherwise indicated, halogen includes fluorine, chlorine,bromine, and iodine.

(C₂-C₉)Heterocyclyl- when used herein refers to, but is not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl and chromanyl. Said (C₂-C₉)heterocyclylring is attached through a carbon or a nitrogen atom.

(C₂-C₉)Heteroaryl when used herein refers to, but is not limited to,furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5 triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl and benzoxazinyl and may be optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of, but not limited, to: H—, HO—, halo-, (C₁-C₈)alkyl-optionally substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— whereinthe alkyl group is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, NC—H₂N—, H₂N—(C₁-C₈)alkyl-, HO—(C═O)—,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, H₂NSO₂—, (C₁-C₈)alkyl-SO₂-NH—.

Aryl when used herein refers to phenyl or naphthyl which may beoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of but not limited to: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-, H₂NSO₂—, (C₁-C₈)alkyl-SO₂—NH—;

The compounds of this invention include all conformational isomers(e.g., cis and trans isomers) and all optical isomers of compounds ofthe formula I (e.g., enantiomers and diastereomers), as well as racemic,diastereomeric and other mixtures of such isomers.

Examples of specific preferred compounds of the formula I are thefollowing:

-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (4-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (3-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (4-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (3-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}    phenyl)-methanesulfonic acid;-   (2-Chloro-6-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-y)-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)₂R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   3-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (2-Bromo-6-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[2E-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoy}-phenyl)-ethanesulfonic    acid;-   3-(5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   2-(5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   3-(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy-phenyl}-propane-1-sulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-propane-1-sulfonic    acid;-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   3-(5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   3-(5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-pipe-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   3-(5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (2-{2-[4-(4-Fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-5-methyl-phenyl)-methanesulfonic    acid;-   2-(5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2 R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2    R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2    R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid,-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2    R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[4-(4-chloro-benzyl)-2    R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   3-(5-Bromo-2-{2-[4-(3,4-difluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-1-sulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[4-(3,4-difluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   (5-Bromo--2-{2-[4-(3,4-difluoro-benzyl)-2 R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[4-(4-chloro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-ethanesulfonic    acid;-   3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-propane-1-sulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-2-sulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propane-2-sulfonic    acid;-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methyl-propane-1-sulfonic    acid;-   2-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methyl-propane-1-sulfonic    acid;-   1-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methyl-propane-2-sulfonic    acid;-   (2-{2-[4-(4-Fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-trifluoromethyl-phenyl)-methanesulfonic    acid;-   (2-{2-[4-(4-Fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-5-trifluoromethyl-phenyl)-methanesulfonic    acid;-   (2-{2-[4-(4-Fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-5-methyl-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-20    phenyl)-methanesulfonic acid;-   (5-Chloro-2-{2-[2    R-ethyl-4-(4-fluoro-benzyl)-5S-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Chloro-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Bromo-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic    acid;-   (5-Chloro-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   (5-Bromo-2-{2-[2R-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic    acid;-   1-(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,    5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-2-methyl-propane-2-sulfonic    acid;-   2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2    R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-phenyl)-ethanesulfonic    acid and-   (5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-phenyl)-methanesulfonic    acid;

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases, rheumatoid arthritis, recent onset type I diabetes, lupus,inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute andchronic inflammatory conditions, osteoarthritis, adult RespiratoryDistress Syndrome, Respiratory; Distress Syndrome of infancy, ischemiareperfusion injury, glomerulonephritis, allergic conditions, asthma,atopic dermatitis, infection associated with inflammation, viralinflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis (including, but not limited to, restenosisfollowing balloon and/or stent insertion), HIV infectivity (co-receptorusage), and granulomatous diseases (including: sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also have utility for theprevention cancer metastasis. Compounds in this series may also limitthe production of cytokines at inflammatory sites, including but notlimited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g., fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprising anamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof effective in treating or preventing such disorder orcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by inhibiting chemokine binding to the receptor CCR1 in amammal, preferably a human, comprising an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof, effective intreating or preventing such disorder or condition and a pharmaceuticallyacceptable carrier. Examples of such disorders and conditions are thoseenumerated in the preceding paragraph.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases,rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatorybowel disease, optic neuritis, psoriasis, multiple sclerosis,polymyalgia rheumatica, uveitis, vasculitis, acute and chronicinflammatory conditions, osteoarthritis, adult Respiratory DistressSyndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusioninjury, glomerulonephritis, allergic conditions, asthma, atopicdermatitis, infection associated with inflammation, viral inflammation,influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis (including, but not limited to, restenosisfollowing balloon and/or stent insertion), HIV infectivity (co-receptorusage), and, granulomatous diseases (including sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also have utility for theprevention of cancer metastasis. Compounds in this series may also limitthe production of cytokines at inflammatory sites, including but notlimited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1; HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g., fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment or prevention anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating or preventing such disorderor condition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byantagonizing the CCR1 receptor in a mammal, preferably a human,comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases, rheumatoid arthritis, recent onset type I diabetes, lupus,inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute andchronic inflammatory conditions, osteoarthritis, adult RespiratoryDistress Syndrome, Respiratory Distress Syndrome of infancy, ischemiareperfusion injury, glomerulonephritis, allergic conditions, asthma,atopic dermatitis, infection associated with inflammation, viralinflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis (including, but not limited to, restenosisfollowing balloon and/or stent insertion), HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also have utility for theprevention of cancer metastasis. Compounds in this series may also limitthe production of cytokines at inflammatory sites, including but notlimited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g., fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprising a CCR1receptor antagonizing effective amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by antagonizing the CCR1 receptor in a mammal, preferably ahuman, comprising a CCR1 receptor antagonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases,rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatorybowel disease, optic neuritis, psoriasis, multiple sclerosis,polymyalgia rheumatica, uveitis, vasculitis, acute and chronicinflammatory conditions, osteoarthritis, adult Respiratory DistressSyndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusioninjury, glomerulonephritis, allergic conditions, asthma, atopicdermatitis, infection associated with inflammation, viral inflammation,influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis (including, but not limited to, restenosisfollowing balloon and/or stent insertion), HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also have utility for theprevention of cancer metastasis. Compounds in this series may also limitthe production of cytokines at inflammatory sites, including but notlimited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g., fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment or prevention a CCR1receptor antagonizing effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated a, b, c,d and R¹ through R⁶ and structural formula I in the reaction Schemes andthe discussion that follow are defined as above The reactions in thePreparations and Schemes are described in commonly assigned co-pendingprovisional applications Ser. No. 60/193,789, filed Mar. 31, 2000, Ser.No. 60/241,084 filed Oct. 19, 2000 and Ser. No. 09/821,322, filed Mar.29, 2001, the disclosure of which is incorporated herein by referencethereto.

In reaction 1 of Preparation A the compound of formula II, wherein b is0, 1 or 2; is converted to the corresponding compound of formula III byreacting II with a benzaldehyde compound of the formula

in the presence of a base, such as triethylamine, and a reducing agent,such as sodium triacetoxyborohydride, in an aprotic solvent, such as1,2-dichloroethane. The reaction mixture is stirred at room temperaturefor a time period between about 1 hour to about 4 hours, preferablyabout 2 hours.

In reaction 2 of Preparation A, the compound of formula III is convertedto the corresponding compound of formula IV by first reacting a compoundof the formula

wherein c is 0, 1 or 2, with 4-methyl morpholine andisobutylchloroformate in the presence of a polar aprotic solvent, suchas tetrahydrofuran, followed by reacting the intermediate so formed withthe compound of formula III. The reaction mixture, so formed, is stirredovernight at ambient temperature.

In reaction 3 of Preparation A, the compound of formula IV is convertedto the corresponding piperizine-2,5-dione compound of formula V bytreating IV with trifluoroacetic acid in the presence of a polar aproticsolvent, such as methylene chloride. The reaction is stirred, at roomtemperature, for a time period between about 1 hour to about 4 hours,preferably about 2 hours.

In reaction 4 of Preparation A, the compound of formula V is convertedto the corresponding compound of formula VI by reducing V with areducing agent, such as lithium aluminum hydride. The reaction isconducted at a temperature between about −10° C. to about 10° C.,preferably about 0° C., for a time period between about 10 minutes toabout 90 minutes, preferably about 40 minutes.

In reaction 5 of Preparation A, the compound of formula VI is convertedto the corresponding compound of formula VII by reacting VI withchloroacetyl chloride in the presence of a base, such as triethylamine,in a polar aprotic solvent, such as methylene chloride, at ambienttemperature for a time period between 15 minutes and 3′ hours,preferably about 30 minutes.

In reaction 6 of Preparation A, the compound of formula VI is convertedto the corresponding compound of formula VIII by reacting VI withacetoxy acetylchloride in the presence of a base, such as triethylamine,in a polar aprotic solvent, such as methylene chloride, at ambienttemperature for a time period between 15 minutes and 4 hours, preferablyabout 1 hour. The resulting acetyl-protected alcohol is reacted withlithium hydroxide hydrate in a solvent mixture including water,tetrahydrofuran and methanol, at ambient temperature for a time periodbetween 1 hour and 8 hours, preferably about 2 hours.

In reaction 1 of Preparation B the compound of formula IX is convertedto the corresponding compound of the formula X by treating IX with areducing agent, such as lithium aluminum hydride, in an aprotic solvent,such as tetrahydrofuran. The reaction mixture is heated to reflux for atime period between 1 hour and 6 hours, preferably about 2 hours.

In reaction 2 of Preparation B the compound of formula X is converted tothe corresponding compound of the formula XI by first converting thehydroxyl group to a chloro group by reacting X with thionyl chloride, inthe presence of an aprotic solvent, such as methylene chloride. Thereaction is heated to reflux, for a time period between about 1 hour toabout 10 hours, preferably about 3 hours. The resulting alkyl chlorideis then treated with a cyanide source, such as potassium cyanide, in thepresence of an aprotic solvent, such as acetonitrile and a crown ether,such as 18-crown-6. The reaction mixture is stirred at ambienttemperature for a time period between about 1 hour to about 10 hours,preferably about 3 hours.

In reaction 3 of Preparation B the compound of formula XI is convertedto the compound of formula XII by first treating XI with a hydroxidesource, such as potassium hydroxide in a mixture of ethanol and water.The reaction mixture is heated to reflux for a time period between about1 hour to about 10 hours, preferably about 8 hours.

In reaction 4 of Preparation B the compound of formula XIII is convertedto the compound of formula XIII by treating with ethanol in the presenceof an acid, such as hydrochloric acid, at ambient temperature for a timeperiod between about 8 hours to about 16 hours, preferably about 12hours.

In reaction 5 of Preparation B the compound of formula XIII is convertedto the corresponding compound of formula XIV, by first treating XIIIwith an reducing agent, as above in reaction 1 of Preparation B. Theresultant alcohol may be converted to XIV with an oxidizing agent, suchas Dess-Martin periodinane, in the presence of an aprotic solvent, suchas tetrahydrofuran at ambient temperature for a time period betweenabout 1 hour to about 16 hours, preferably about 4 hours.

In reaction 6 of Preparation B the compound of formula X is converted tothe corresponding compound of formula XV by first treating X with anoxidizing agent, such as Dess-Martin periodinane, in the presence of anaprotic solvent, such as tetrahydrofuran at ambient temperature for atime period between about 1 hour to about 16 hours, preferably about 4hours.

In reaction 7 of Preparation B the compound of formula XV is convertedto the corresponding compound of formula XVI, wherein e may equal 2-7,by first treating with phosphonium ylide derived from the phosphoniumsalt of the formula:

wherein f may be (C₁₋₆)-alkyl, wherein alkyl is defined as above, in thepresence of an aprotic solvent, such as tetrahydrofuran. The reaction isconducted at a temperature between −78° C. and reflux, the preferredtemperature is dependent on which phosphonium-ylide is utilized, for atime period between about 4 hours to about 16 hours, preferably abouthours (For similar transformations, see: J. Am. Chem. Soc. 1985, 107,217). The resulting olefinic ester is then hydrogenated by shaking undera positive pressure of hydrogen in the presence of a catalyst, such asplatinum dioxide, in the presence of an aprotic solvent such as ethylacetate. The ester is then reduced and reoxidized according to theprocedure described in reaction 5 of Preparation B to afford compound offormula XVI.

In reaction 8 of Preparation C compounds of formula XIV, XV or XVI areconverted to the corresponding compound of formula XVIII, wherein gequals 0-7, by demethylating the methyl ether with acid, such as 47%aqueous hydrogen bromide. The reaction mixture is heated to reflux for atime period between about 10 hours to about 30 hours, preferably about24 hours.

In reaction 1 of Scheme 1, the compound of formula VII is converted tothe corresponding compound of formula XVIII, wherein g equals 0-7, byreacting VII with a compound of the formula XVII in the presence ofpotassium carbonate, potassium iodide and an aprotic solvent, such asdimethylformamide. The reaction is heated to reflux for a time periodbetween about 4 hours to about 8 hours, preferably about 6 hours.

In reaction 2 of Scheme 1, the compound of formula XVIII is converted tothe corresponding compound of formula XIX, wherein g equals 0-7, byreacting XVIII with a reducing agent, such as sodium borohydride, in anaprotic solvent, such as tetrahydrofuran, at a temperature between about−10° C. and ambient temperature, preferably ambient for a time periodbetween 15 minutes and 90 minutes, preferably about 60 minutes.

In reaction 3 of Scheme 1, the compound of formula XIX is converted tothe corresponding compound of formula XX, wherein g equals 0-7, asdescribed in reaction 2 of preparation B.

In reaction 4 of Scheme 1, the compound of formula XX is converted tothe corresponding compound of formula I by reacting XX with sodiumsulfite in water, at a temperature between 70° C. and 100° C.,preferably 100° C. for a time period between 1 and 5 hours, preferablyabout 1 hour. The addition of catalytic sodium iodide may beadvantageous.

In reaction 1 of Scheme 2, the compound of formula VIII is converted tothe corresponding compound of formula XXI by reacting VII with acompound of formulaCl—Y[(R⁴)_(d)]—(CH₂)_(h)—CHOwhere Y is a (C2-C9) heteroaryl wherein the chlorine is attached to acarbon atom that is adjacent to a heteroatom (for example, 2-pyridyl)and wherein h equals 0-7. The reactants are stirred in a polar aproticsolvent, such as acetonitrile, in the presence of a base, such astriethylamine, at reflux temperature for a time period between about 4hours and 24 hours, preferably about 12 hours.

In reaction 2 of Scheme 2, the compound of formula XXI, where Y is a(C₂-C₉) heteroaryl, may be converted into I using the methodologiesdescribed above in Scheme 1.

In reaction 1 of Scheme 3, the compound of formula VII may be convertedto the corresponding compound of formula XXII, where Y is a (C₂-C₉)heteroaryl, by reacting VII with tert-butoxycarbonylamino-acetic acid inan aprotic solvent, such as methylene chloride, with a carbodiimide,such dicyclohexylcarbodiimide, in the presence of a base, such astriethylamine, at room temperature for a time period between about 1 and24 hours, preferably about 3 hours. The compound of formula XXII maysubsequently be produced from this carbamate by the action oftrifluoroacetic acid at room temperature for a time period between about1 and 12 hours, preferably about 4 hours.

In reaction 2 of Scheme 3, the compound of formula XXII may be convertedto the corresponding compound of formula XXII, where Y is a (C₂-C₉)heteroaryl, following the precedent set forth in reaction 1 of Scheme 2.

In reaction 3 of Scheme 3, the compound of formula XXIII may beconverted to the corresponding compound of formula XXIV, where Y is a(C₂-C₉) heteroaryl, by first reducing the ester to the correspondingalcohol with a reducing agent, such as sodium borohydride, intert-butanol and methanol, at a temperature between about 20° C. andreflux, preferably reflux for a time-period between 1 hour and 6 hours,preferably about 1 hour. The resultant alcohol may be converted to thecompound of formula XXIV by treating with an oxidizing agent, such asDess-Martin periodinane, in the presence of an aprotic solvent, such astetrahydrofuran at ambient temperature for a time period between about 1hour to about 16 hours, preferably about 4 hours.

In reaction 4 of Scheme 3, the compound of formula XXIV, where Y is a(C₂-C₉) heteroaryl, may be converted into I using the methodologiesdescribed above in Scheme 1.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reactions mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts, of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, a solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

Those compounds of the formula I which are also acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described, acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium- andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are potent antagonists of the CCR1 receptor. The active compounds areuseful in the treatment or prevention of autoimmune diseases (such asrheumatoid arthritis, type I diabetes (recent onset), lupus,inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute andchronic inflammatory conditions (such as osteoarthritis, adultRespiratory Distress Syndrome, Respiratory Distress Syndrome of infancy,ischemia reperfusion injury, glomerulonephritis, and chronic obstructivepulmonary disease (COPD)), allergic conditions (such as asthma andatopic dermatitis), inflammation associated with infection (such asviral inflammation (including influenza, hepatitis and Guillian-Barre),chronic bronchitis, chronic and acute tissue, cell, and solid organtransplant rejection (including xeno-transplantation), atherosclerosis,restenosis, HIV infectivity (co-receptor usage), and granulomatousdiseases (including sarcoidosis, leprosy and tuberculosis) and sequelaeassociated with certain cancers such as multiple myeloma. Compounds inthis series may also have utility for the prevention of cancermetastasis, as well as restenosis following balloon and/or stentinsertion. Compounds in this series may also limit the production ofcytokines at inflammatory sites, including but not limited to TNF andIL-1, as a consequence of decreasing cell infiltration, providingbenefit for diseases linked to TNF and IL-1 including congestive heartfailure, pulmonary emphysema or dyspnea associated therewith, emphysema;HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses(Herpes zoster and Herpes simplex). They may also provide benefit forthe sequelae associated with infection where such infection inducesproduction of detrimental inflammatory cytokines such as TNF e.g.,fungal meningitis, joint tissue damage, hyperplasia, pannus formationand bone resorption, psoriatic arthritis, hepatic failure, bacterialmeningitis, Kawasaki syndrome, myocardial infarction, acute liverfailure, lyme disease, septic shock, cancer, trauma, and malaria, etc.

The activity of the compounds of the invention can be assessed accordingto procedures know to those of ordinary skill in the art. Examples ofrecognized methods for determining CCR1 induced migration can be foundin Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M.,Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3.(John Wiley and Sons, NY, 1991). One specific example of how todetermine the activity of a compound for inhibiting migration isdescribed in detail below.

Chemotaxis Assay:

The ability of compounds to inhibit the chemotaxis to various chemokinecan be evaluated using standard 48 or 96 well Boyden Chambers with a 5micron polycarbonate filter. All reagents and cells can be prepared instandard RPMI (BioWhitikker Inc.) tissue culture medium supplementedwith 1′ mg/mL of bovine serum albumin. Briefly, MIP-1α (Peprotech, Inc.,P.O. Box 275, Rocky Hill N.J.) or other test agonists, are placed intothe lower chambers of the Boyden chamber. A polycarbonate filter is thenapplied and the upper chamber fastened. The amount of agonist chosen isthat determined to give the maximal amount of chemotaxis in this system(e.g., 1 nM for MIP-1α should be adequate).

THP-1 cells (ATCC TIB-202), primary human monocytes, or primarylymphocytes, isolated by standard techniques can then be added to theupper chambers in triplicate together with various concentrations of thetest compound. Compound dilutions can be prepared using standardserological techniques and are mixed with cells prior to adding to thechamber.

After a suitable incubation period at 37 degrees centigrade (e.g. 3.5hours for THP-1 cells, 90 minutes for primary monocytes), the chamber isremoved, the cells in the upper chamber aspirated, the upper part of thefilter wiped and the number of cells migrating can be determinedaccording to the following method.

For THP-1 cells, the chamber (a 96 well variety manufactured byNeuroprobe) can be centrifuged to push cells off the lower chamber andthe number of cells can be quantitated against a standard curve by acolor change of the dye fluorocein diacetate.

For primary human monocytes, or lymphocytes, the filter can be stainedwith Dif Quik® dye (American Scientific Products) and the number ofcells migrating can be determined microscopically.

The number of cells migrating in the presence of the compound aredivided by the number of cells migrating in control wells (without thecompound). The quotant is the % inhibition for the compound which canthen be plotted using standard graphics techniques against theconcentration of compound used. The 50% inhibition point is thendetermined using a line fit analysis for all concentrations tested. Theline fit for all data points must have an coefficient of correlation (Rsquared) of >90% to be considered a valid assay.

All of the compounds of the invention illustrated in the followingexamples had IC₅₀ of less than 10 μM, in the Chemotaxis assay.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. Theactive-compounds of the invention may also be formulated for sustaineddelivery.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to abovee.g., rheumatoid arthritis) in the average adult human are preferablyarranged so that each metered dose or “puff” of aerosol contains 20 μgto 1000 μg of the compound of the invention. The overall daily dose withan aerosol will be within the range 0.1 mg to 1000 mg. Administrationmay be several times daily, for example 2, 3, 4 or 8 times, giving forexample, 1, 2 or 3 doses each time.

The active agents can be formulated for sustained delivery according tomethods well known to those of ordinary skill in the art. Examples ofsuch formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598,4,173,626, 3,119,742, and 3,492,397.

The compounds of the invention can also be utilized in combinationtherapy with immunosuppressant agents including but not limited torapamycin, cyclosporin A, FK-506, Cellcept®; azathioprine, and IL-2Rinhibitory antibodies or with classical anti-inflammatory agents (e.g.cyclooxygenase/lipoxygenase inhibitors) such as but not limited to,aspirin, acetaminophen, naproxen and piroxicam or with cytokineinhibitory agents including but not limited to ENBREL.

The following Examples illustrate the preparation of the compounds ofthe present invention. Commercial reagents were utilized without furtherpurification. Chromatography refers to column chromatography performedusing 32-63 mm silica gel and executed under nitrogen pressure (flashchromatography) conditions. Particle Beam Mass Spectra were recorded oneither a Hewlett Packard 59890, utilizing chemical ionization(ammonium), or a Fisons (or MicroMass) Atmospheric Pressure ChemicalIonization (APCI) platform which uses a 50/50 mixture ofacetonitrile/water. Room or ambient temperature refers to 20-25° C. Allnon-aqueous reactions were run under a nitrogen atmosphere forconvenience and to maximize yields. Concentration in vacuo means that arotary evaporator was used. The names for the compounds of the inventionwere created by the Autonom 2.0 PC-batch version from BeilsteinInformationssysteme GmbH (ISBN 3-89536-976-4)

EXAMPLE 1

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2+-phenyl)-methanesulfonic acid (S)-2-(4-Fluoro-benzylamino)-propionicacid methyl ester

To a solution of (S)-2-amino-propionic acid methyl ester hydrochloride(25 g, 179 mmol) and 4-fluorobenzaldehyde (23 mL, 215 mmol) in1,2-dichloroethane (200 mL) was added triethylamine (25 mL, 179 mmol).The resulting mixture was stirred for two hours at ambient temperaturefollowed by addition of sodium triacetoxyborohydride (57 g, 268 mmol),in four portions. The resulting mixture was stirred overnight at ambienttemperature. The reaction was neutralized with dilute aqueous sodiumhydroxide solution and extracted with dichloromethane. The organic layerwas dried over magnesium sulfate, filtered and concentrated in, vacuo.Chromatography on silica gel gave the title compound (34.4 g).

(2S)-2-[(2R)-(2-tert-Butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionicacid methyl ester

To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g,195 mmol) in dry tetrahydrofuran (250 mL) at 0° C. was added 4-methylmorpholine (21.5 mL, 195 mmol), followed by isobutylchloroformate (25.3mL, 195 mmol). The reaction was allowed to warm to ambient temperatureand stirred for two hours. This was followed by the addition of(S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162mmol). The resulting mixture was stirred overnight at ambienttemperature. The reaction mixture was filtered through a pad of celiteand the filter cake was washed with ethyl acetate. The filtrate wasconcentrated in vacuo, diluted with ethyl acetate and washed with waterand brine. The organic layer was dried over magnesium sulfate, filteredand concentrated in vacuo. Chromatography on silica gel gave the titlecompound (43.2 g).

(3R,6S)-1-(4-Fluoro-benzyl)-3.6-dimethyl-piperazine-2,5-dione

To a solution of(2S)-2-[(2R)-(2-tert-butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionicacid methyl ester (43 g, 382 mmol) in dichloromethane (120 mL) at 0° C.was added trifluoroacetic acid (60 mL). The reaction was allowed to warmto ambient temperature and stirred for 2 h ours. The reaction w cooledto 0° C. and slowly quenched by addition of 3 N sodium hydroxide untilbasic. The resulting mixture was extracted with dichloromethane. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to give the title compound (22 g).

(2R, 5S)-1-(4-Fluoro-benzyl)-2,5-dimethyl-piperazine

To a solution of (3R,6S)-1-(4-fluoro-benzyl)-3,6-dimethyl-piperazine-2,5-d one (22 g, 87.9mmol) in dry tetrahydrofuran (160 mL) at 0° C. was added a solution oflithium, aluminum hydride (1M in tetrahydrofuran, 373 mL, 373 mmol)dropwise over 40 minutes. The reaction mixture was then refluxed for 4hours, cooled to ambient temperature and slowly quenched with water. Theresulting mixture was filtered through a pad of celite and the filtercake was washed with ethyl acetate. The filtrate was then concentrated,diluted with ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate. The ‘organic’ layer was separated, dried overmagnesium sulfate, filtered and concentrated in vacuo to give the titlecompound (17.7 g).

2-Chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of (2R, 5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine(2.59 g, 11.2 mmol) in dry dichloromethane (11 mL) at 0° C. was addedtriethylamine (1.57 mL, 11.2-mmol) followed by chloroacetyl chloride(0.86 mL, 1-1.2 mmol). The resulting reaction mixture was stirred for 30minutes. The reaction was then filtered through a pad of celite; washedwith dichloromethane and the resulting filtrate was concentrated.Chromatography on silica gel gave the title compound (2.84 g).

5-Chloro-2-(2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy]-benzaldehyde

To a solution of2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone(2.87 g, 9.6 mmol) in dimethylformamide (20 mL) was added5-chlorosalicylaldehyde (1.65 g, 10.5 mmol), potassium carbonate (2.64g, 19.2 mmol) and potassium iodide (1.59 g, 9.6 mmol). The resultingmixture was heated to 100° C. for 12 hours. The reaction was cooled,diluted with saturated aqueous brine and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo to give crude product. Purificationvia chromatography on, silica gel gave the title compound (3.40 g).

2-(4-Chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-1-yl]-ethanone

To a solution of5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde(0.99 g, 2.36 mmol) in dry methanol (25 mL) was added sodium borohydride(0.19 g, 4.92 mmol). After 1 hour the reaction was acidified to pH 2 bythe addition of 1N hydrochloric acid. After 5 minutes the reaction wasneutralized with 1N sodium hydroxide and the methanol removed byevaporation. The resulting aqueous suspension was extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and evaporated to give the title compound (0.98 g).

2-(4-Chloro-2-chloromethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-2.5-dimethyl-piperazin-1-yl]-ethanone

To2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone(0.55 g, 1.3 mmol) in methylene chloride (6 ml) was added thionylchloride (0.26 ml, 3.58 mmol). The reaction was heated to reflux for 2hours. After cooling the reaction was quenched by the addition of water.The organic layer was washed with saturated sodium bicarbonate followedby saturated aqueous sodium chloride. The organic layer was thenconcentrated to afford the title compound as a yellow oil (0.52 g).

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonicacid

To2-(4-chloro-2-chloromethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone(0.52 g, 1.2 mmol) in 1:1 ethahol:water (6 mL) was added sodium sulfite(0.75 g, 5.97 mmol). The reaction was heated to reflux for 12 hours.After cooling the reaction was concentrated and purified bychromatography on silica gel to afford the title compound (0.39 g) as asodium salt.

EXAMPLE 2

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonicacid (3R)-1-(4-Fluoro-benzyl)-3-methyl-piperazine

To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol(80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) andsodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxedovernight, cooled and concentrated. The remaining residue was dilutedwith dichloromethane and washed with water. The organic layer wasseparated and concentrated to give a clear oil. Chromatography on silicagel gave the title compound (5.0 g).

2-Chloro-1-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-ethanone

To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4mmol). The reaction was cooled to 0° C. and chloroacetyl chloride wasadded (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambienttemperature and stirred for 2 hours. The reaction was diluted withdichloromethane and washed with 10% citric acid. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated invacuo. Chromatography on silica gel gave the title compound (3.9 g).

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde

To a solution of2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone(0.1 g, 0.352 mmol) in dimethylformamide (5 mL) was added5-chlorosalicylaldehyde (60 mg, 0.387 mmol), potassium carbonate (97 mg,0.704 mmol) and potassium iodide (58 mg, 0.352 mmol). The resultingmixture was heated to 65° C. for 2 hours. The reaction was cooled andthe dimethylformamide was removed in vacuo. The crude reaction wasdiluted with ethyl acetate, washed with saturated aqueous and theorganic layer was dried over magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo to give the title compound (140 mg)which was used directly in the following step.

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic acid

To a solution of5-chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde(90 mg, 0.223 mmol) in tetrahydrofuran (2 mL) was added sodiumborohydride (25 mg, 0.667 mmol). After 1 hour the reaction was dilutedwith ethyl actate and washed with water followed by brine. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to afford the corresponding alcohol, which was taken on to thenext step.

To2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2R-methyl-piperazin-1-yl]-ethanone(0.223 mmol) in methylene chloride (3 ml) was added thionyl chloride(0.04 ml, 0.558 mmol). The reaction was heated to reflux for 1 hour.After cooling the reaction was diluted with additional methylenechloride, washed with saturated aqueous sodium bicarbonate followed bybrine. The organic layer was then dried over magnesium sulfate andconcentrated in vacuo to afford the corresponding chloride as a yellowoil, which was taken on to the next step.

To2-(4-chloro-2-chloromethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]-ethanone(0.223 mmol) in 1:1 ethanol:water (2 mL) was added sodium sulfite (0.75g, 5.97 mmol). The reaction was heated to reflux for 12 hours. Aftercooling the reaction was concentrated in vacuo and purified bychromatography on silica gel to afford the title compound (example 2) asa sodium salt (10 mg).

EXAMPLE 3

2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonicacid (5-Chloro-2-methoxy-phenyl)-methanol

To a solution of 5-chloro-2-methoxy-benzoic acid methyl ester (20 g,9.97 mmol) in THF (100 mL) at 0° C. was added dropwise a solution oflithium aluminum hydride (210 mL, 210 mmol, 1M soln. in THF). Thesolution was then warmed to reflux for 2 hours. The reaction was cooledto 0° C. and carefully quenched by the addition of cold water. Themixture was filtered through celite and the filter cake was washed withdiethyl ether. The filtrate was washed with saturated aqueous sodiumhydrogen carbonate then dried over magnesium sulfate. Concentration invacuo gave the title compound (17.2 g).

(5-Chloro-2-methoxy-Phenyl)-acetonitrile

To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled toroom temperature and concentrated in vacuo. The crude product wasdissolved in methylene chloride and washed with saturated aqueous sodiumhydrogen carbonate then dried over magnesium sulfate. Concentration invacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4° g). To asolution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12hours at ambient temperature, diluted with ethyl acetate and washed withaqueous sodium hydrogen carbonate. The organic layer was dried overmagnesium sulfate and concentrated in vacuo. The crude product waspurified by passing it through a pad of silica gel, eluting withmethylene chloride to give the title compound (17.2 g).

(5-Chloro-2-methoxy-phenyl)-acetic acid

To a solution of (5-chloro-2-methoxy-phenyl)-acetonitrile (17.2 g, 96.3mmol) in ethanol (200 mL) and water (20 mL) was added potassiumhydroxide (27 g, 481 mmol). The reaction was heated to reflux for 12hours, cooled and the ethanol was removed by concentrating in vacuo. Theremaining solution was acidified with aqueous hydrochloric acid (3 M)and extracted with diethyl ether. The organic layer was dried overmagnesium sulfate and concentrated in vacuo to give the title compound(15.6 g).

(5-Chloro-2-hydroxy-phenyl)-acetic acid ethyl ester

A solution of (5-chloro-2-methoxy-phenyl)-acetic acid (15.5 g, 77.5mmol) in 48% aqueous hydrogen bromide was heated to reflux for 20 hours.The solution was cooled diluted with water and extracted with diethylether. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude product was purified by trituration in2:1 methylene chloride:hexanes to give (5-chloro-2-hydroxy-phenyl)-oacetic-acid (12.8 g). This was dissolved in a solution of ethanolsaturated with hydrochloric acid, and stirred 12 hours. The reaction wasconcentrated in vacuo, then the crude product was dissolved in diethylether and washed with saturated aqueous sodium hydrogen carbonate. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to give the title compound (12.7 g).

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-aceticacid ethyl ester

To a solution of2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone(3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added(5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol),potassium-carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g,11.0 mmol). The reaction was heated at reflux for 48 hrs. The solutionwas cooled, diluted with ethyl acetate and washed with brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude product was purified by dissolving indichloromethane and passing through a pad of silica gel. Concentrationin vacuo gave the title compound (5.13 g).

2-[4-Chloro-2-(2-hydroxy-ethyl)-phenoxy]-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone

To a solution of(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-aceticacid ethyl ester (0.05 g, 0.1 mmol) in tert-butanol (1 ml) was addedlithium borohydride (0.01 g, 0.26 mmol). The reaction was heated toreflux and methanol (0.2 ml) was added over one hour. After 1 hour thereaction was diluted with with ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo and purified by silica gel chromatography to givethe title compound (0.04 g).

2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonicacid

To2-[4-chloro-2-(2-hydroxy-ethyl)-phenoxy]-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone(0.072 g, 0.166 mmol) in methylene chloride (2 ml) was added thionylchloride (0.1 ml, 0.83 mmol). The reaction was stirred at roomtemperature for 14 hours and heated to reflux for an additional 3 hours.After cooling the reaction was quenched by the addition of water anddiluted with additional methylene chloride. The organic layer was washedwith saturated sodium bicarbonate followed by saturated aqueous sodiumchloride.

The organic layer was then concentrated to afford the correspondingchloride as a brown oil (0.075 g).

To2-[4-chloro-2-(2-chloro-ethyl)-phenoxy]-1-[4-(4-fluoro-benzyl)-2R,5S-dimethylpiperazin-1-yl]-ethanone (0.075 g, 0.166 mmol) in 1:1 ethanol:water (5mL) was added sodium sulfite (0.1 g, 0.79 mmol) and sodium iodide (0.024g, 0.16 mmol). The reaction was heated to reflux for 20 hours. Aftercooling the reaction was concentrated and purified by chromatography onsilica gel to afford the title compound (6.0 mg) as a sodium salt.

EXAMPLE 4

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethox-pyridin-3-yl)-methanesulfonic acid Acetic acid2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethyl ester

To 1-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazine (2 g, 9 mmol) inmethylene chloride (45 ml) at 0° C. was added triethylamine (1.36 ml,9.9 mmol) followed by acetic acid chlorocarbonylmethyl ester (1.06 ml,9.9 mmol). After three hours the reaction was washed with saturatedsodium bicarbonate. The organic layer was dried over magnesium sulfate,filtered, concentrated and purified by chromatography on silica gel toafford the title compound (2.6 g).

1-[4-(4-fluoro-benzyl)-(2R,5S)-2.5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone

To acetic acid2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethyl ester(2.6 g, 8 mmol) in tetrahydrofuran/methanol/water (2:2:1, 40 ml) wasadded lithium hydroxide hydrate (0.5 g, 12 mmol). After two hours thereaction was concentrated to dryness and taken up in ethyl acetate. Theorganic layer was washed with saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated to afford the titlecompound (2.12 g).

5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-nicotinic acid methyl ester

To1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone(0.05 g, 0.178 mmol) in tetrahydrofuran (1 ml) at 0° C. was added sodiumhydride (11 mg, 0.275 mmol) followed by 18-crown-6 (26 mg, 0.10 mmol).After 15 minutes the reaction was allowed to warm to ambient temperatureand 2,5-dichloro-nicotinic acid methyl ester (55 mg, 0.267 mmol) (frommodification of J. Med. Chem., 1997, 40, 2674) in tetrahydrofuran (0.25ml) was slowly added. After two hours the reaction was quenched withsaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulfate, filtered and concentrated in vacuo.Chromatography on silica gel gave the title compound (25 mg).

2-(5-Chloro-3-hydroxymethyl-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone

To5-chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-nicotinicacid methyl ester (24 mg, 0.053 mmol) and sodium borohydride (5 mg,0.132 mmol) in tert-butanol (1 ml) at reflux was added methanol (0.04ml, 1.06 mmol). After 90 minutes the reaction was cooled to ambienttemperature and the solvent removed in vacuo. The reaction was taking upin water and extracted three times with methylene chloride. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and concentrated in vacuo. Chromatography on silica gel gavethe title compound (22 mg).

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonicacid

To2-(5-chloro-3-hydroxymethyl-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone(0.067 g, 0.159 mmol) in methylene chloride (1.5 ml) was added thionylchloride (0.04 ml, 0.49 mmol). The reaction was stirred at roomtemperature for one hour. The reaction was quenched by the addition ofwater and diluted with additional methylene chloride. The organic layerwas washed with saturated aqueous sodium chloride and dried overmagnesium sulfate. The organic layer was then concentrated to afford thecorresponding chloride as a brown oil (0.07 g).

To2-(5-chloro-3-chloromethyl-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin-1-yl]-ethanone(0.05 g, 0.161 mmol) in 1:1 ethanol:water (1 mL) was added sodiumsulfite (0.07 g, 0.58 mmol). The reaction was heated to reflux for 20hours. After cooling the reaction was concentrated and purified bychromatography on silica gel to afford the title compound (46 mg) as asodium salt.

EXAMPLES 1-5

The compounds from Table 1 were prepared according to the methodsdescribed above. Example # IUPAC LRMS 1(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin- 485.31-yl]- 2-oxo-ethoxy}-phenyl)-methanesulfonic acid 2(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]- 469.12-oxo-ethoxy}-phenyl)-methanesulfonic acid 32-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl- 499.4piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-ethanesulfonic acid 4(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin- 486.41-yl]-2-oxo-ethoxy}-pyridin-3-yl)-methanesulfonic acid 5(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R,5S-dimethyl-piperazin- 529.11-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonic acid 6(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-2R-methyl-piperazin-1-yl]- 513.22-ethoxy}-phenyl)-methanesulfonic acid

1. A compound of the formula

or the pharmaceutically acceptable salts and prodrugs thereof; whereina=0-5, b=0-2, c=0-2 d=0-4 X is —O—, —S—, —CH₂—, —NR⁶— Y is (C₆-C₁₀)aryl,or (C₂-C₉)heteroaryl, each R¹ is independently selected from the groupconsisting of: H—, HO—, halo-, (C₁-C₈)alkyl- optionally substituted with1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkyl group isoptionally substituted with 1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—,H₂N—, H₂N—(C₁-C₈)alkyl-, HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—,(C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-;each R² and R³ is independently selected from the group consisting of:H—, oxo, (C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-, (C₆-C₁₀)aryl-(C₁-C₈)alkyl-,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-, H₂N—(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-SO₂—NH—(C₁-C₈)alkyl-, (C₂-C₉)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH-(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-Cg)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-. 2-25.(canceled)
 26. A pharmaceutical composition for treating or preventing adisorder or condition selected from adult Respiratory Distress Syndrome,asthma, atopic dermatitis, chronic and acute organ transplant rejection,glomerulonephritis, Guillian-Barre, hepatitis, HIV-1, HIV-2, HIV-3,inflammatory bowel disease, influenza, ischemia reperfusion injury,leprosy, multiple sclerosis, optic neuritis, osteoarthritis, polymyalgiarheumatica, psoriasis, psoriatic arthritis, recent onset type Idiabetes, Respiratory Distress Syndrome of infancy, rheumatoidarthritis, sarcoidosis, trauma, tuberculosis, uveitis, vasculitis in amammal, comprising an amount of a compound of the formula

or the pharmaceutically acceptable salts thereof; wherein a=0-5, b=0-2,c=0-2 d=0-4 X is —O— Y is (C₆-C₁₀)aryl, or (C₂-C₉)heteroaryl, each R¹ isindependently selected from the group consisting of: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R² and R³ is independentlyselected from the group consisting of: H—, oxo, (C₁-C₈)alkyl-substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C I—C₈)alkyl-, H₂N—(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-SO₂—NH—(C₁-C₈)alkyl-, (C₂-Cg)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH-(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-C₉)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-, that iseffective in treating or preventing such disorders or conditions and apharmaceutically acceptable carrier.
 27. A method for treating orpreventing a disorder or condition selected from adult RespiratoryDistress Syndrome, asthma, atopic dermatitis, chronic and acute organtransplant rejection, glomerulonephritis, Guillian-Barre, hepatitis,HIV-1, HIV-2, HIV-3, inflammatory bowel disease, influenza, ischemiareperfusion injury, leprosy, multiple sclerosis, optic neuritis,osteoarthritis, polymyalgia rheumatica, psoriasis, psoriatic arthritis,recent onset type I diabetes, Respiratory Distress Syndrome of infancy,rheumatoid arthritis, sarcoidosis, trauma, tuberculosis, uveitis,vasculitis in a mammal, comprising administering to a mammal an amountof a compound of the formula

or the pharmaceutically acceptable salts thereof; wherein a=0-5, b=0-2,c=0-2 d=0-4 X is —O— Y is (C₆-C₁₀)aryl, or (C₂-C₉)heteroaryl, each R¹ isindependently selected from the group consisting of: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R² and R³ is independentlyselected from the group consisting of: H—, oxo, (C₁-C₈)alkyl-substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-, H₂N—(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-SO₂—NH—(C₁-C₈)alkyl-, (C₂-Cg)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH-(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-Cg)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-, that iseffective in treating or preventing such disorders or conditions.
 28. Apharmaceutical composition for treating or preventing a disorder orcondition that can be treated or prevented by antagonizing the CCR1receptor in a mammal selected from adult Respiratory Distress Syndrome,asthma, atopic dermatitis, chronic and acute organ transplant rejection,glomerulonephritis, Guillian-Barre, hepatitis, HIV-1, HIV-2, HIV-3,inflammatory bowel disease, influenza, ischemia reperfusion injury,leprosy, multiple sclerosis, optic neuritis, osteoarthritis, polymyalgiarheumatica, psoriasis, psoriatic arthritis, recent onset type Idiabetes, Respiratory Distress Syndrome of infancy, rheumatoidarthritis, sarcoidosis, trauma, tuberculosis, uveitis, vasculitis in amammal, comprising a CCR1 receptor antagonizing effective amount of acompound of the formula

or the pharmaceutically acceptable salts thereof; wherein a=0-5, b=0-2,c=0-2 d=0-4 X is —O— Y is (C₆-C₁₀)aryl, or (C₂-C₉)heteroaryl, each R¹ isindependently selected from the group consisting of: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R² and R³ is independentlyselected from the group consisting of: H—, oxo, (C₁-C₈)alkyl-substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-, H₂N—(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-SO₂—NH—(C I—C₈)alkyl-, (C₂-C₉)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-Cg)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-, and apharmaceutically acceptable carrier.
 29. A method for treating orpreventing a disorder or condition selected from adult RespiratoryDistress Syndrome, asthma, atopic dermatitis, chronic and acute organtransplant rejection, glomerulonephritis, Guillian-Barre, hepatitis,HIV-1, HIV-2, HIV-3, inflammatory bowel disease, influenza, ischemiareperfusion injury, leprosy, multiple sclerosis, optic neuritis,osteoarthritis, polymyalgia rheumatica, psoriasis, psoriatic arthritis,recent onset type I diabetes, Respiratory Distress Syndrome of infancy,rheumatoid arthritis, sarcoidosis, trauma, tuberculosis, uveitis,vasculitis in a mammal, comprising administering to a mammal in need ofsuch treatment or prevention a CCR1 receptor antagonizing effectiveamount of a compound of the formula

or the pharmaceutically acceptable salts thereof; wherein a=0-5, b=0-2,c=0-2 d=0-4 X is —O— Y is (C₆-C₁₀)aryl, or (C₂-C₉)heteroaryl, each R¹ isindependently selected from the group consisting of: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R² and R³ is independentlyselected from the group consisting of: H—, oxo, (C₁-C₈)alkyl-substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₃-Cg)cycloalkyl-,(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-, H₂N—(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-SO₂—NH—(C₁-C₈)alkyl-, (C₂-C₉)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH-(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-C₉)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-.
 30. Amethod for treating or preventing a disorder or condition selected fromautoimmune diseases, lupus, acute and chronic inflammatory conditions,allergic conditions, infection associated with inflammation, viral,chronic bronchitis, xeno-transplantation, transplantation tissuerejection, atherosclerosis, restenosis, HIV infectivity, andgranulomatous in a mammal, comprising administering to a mammal in needof such treatment or prevention a CCR1 receptor antagonizing effectiveamount of a compound of the formula

or the pharmaceutically acceptable salts thereof; wherein a=0-5, b=0-2,c=0-2 d=0-4 X is —O— Y is (C₆-C₁₀)aryl, or (C₂-C₉)heteroaryl, each R¹ isindependently selected from the group consisting of: H—, HO—, halo-,(C₁-C₈)alkyl- optionally substituted with 1-3 fluorine atoms,(C₁-C₈)alkyl-O— wherein the alkyl group is optionally substituted with1-3 fluorine atoms, HO—(C₁-C₈)alkyl-, NC—, H₂N—, H₂N—(C₁-C₈)alkyl-,HO—(C═O)—, (C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R² and R³ is independentlyselected from the group consisting of: H—, oxo, (C₁-C₈)alkyl-substituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₆-C₁₀)aryl-(C₁-C₈)alkyl-, HO—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₂-C₉)heterocyclyl-(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-O—(C═O)—NH—(C₁-C₈)alkyl-, H₂N—(C═O)—NH—(C—C₈)alkyl-,(C—C₈)alkyl-SO₂—NH—(C₁-C₈)alkyl-, (C₂-C₉)heteroaryl-(C₁-C₈)alkyl-,H₂N—(C═O)—, H₂N—(C═O)—(C₁-C₈)alkyl-; each R⁴ is independently selectedfrom the group consisting of: H—, HO—, halo-, NC—, HO—(C═O)—, H₂N—,(C₁-C₈)alkyl-NH—, [(C₁-C₈)alkyl]₂N—, (C₁-C₈)alkyl- optionallysubstituted with 1-3 fluorine atoms, (C₁-C₈)alkyl-O— wherein the alkylgroup is optionally substituted with 1-3 fluorine atoms,HO—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-O—(C₁-C₈)alkyl-, H₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-NH-(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C₁-C₈)alkyl-,(C₁-C₈)alkyl-(C═O)—, (C₁-C₈)alkyl-(C═O)—(C₁-C₈)alkyl-, (C₆-C₁₀)aryl-,(C₂-Cg)heteroaryl-, (C₆-C₁₀)aryloxy-, H₂N—(C═O)—,H₂N—(C═O)—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-NH—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—(C₁-C₈)alkyl-, [(C₁-C₈)alkyl]₂N—(C═O)—,[(C₁-C₈)alkyl]₂—N—(C═O)—(C₁-C₈)alkyl-, (C₃-C₈)cycloalkyl-,(C₁-C₈)alkyl-SO₂—, NC—(C₁-C₈)alkyl-, (C₁-C₈)alkyl-(C═O)—NH—,H₂N—(C═O)—NH—, H₂N—(C═O)—NH—(C₁-C₈)alkyl-; R⁵ is (C₁-C₈)alkyl-.